Abstract

BACKGROUND: Hereditary spastic paraplegia (HSP or SPG) consists of a heterogeneous group of disorders, clinically divided into pure and complex forms. The former is characterized by neurological impairment limited to lower-extremity spasticity. The latter presents additional symptoms such as seizures, psychomotor impairment, cataract, deafness, and peripheral neuropathy. The genetic structure of HSP is diverse, with more than 72 loci and 55 genes identified so far. The most common type is SPG4, accounting for 40% of cases. This case report describes 2 siblings presenting SPG4, one presumptive and one confirmed with a homozygous SPAST variant.

CASE REPORT: Two siblings born to third-degree consanguineous and healthy parents presented a SPG4 complex phenotype characterized by progressive psychomotor deterioration, mixed seizure patterns, corneal opacity, dysostotic bones, limb spasticity with extensor plantar responses, and axial hypotonia. After ruling out most inborn errors of metabolism in one of the patients, the complexity of the case derived from exome sequencing. The identification of a homozygous variant in the SPAST gene established a diagnosis for SPG4. The phenotype-genotype did not correlate to classical manifestations, most likely due to the variant’s zygosity. Moreover, 34 patient’s relatives were identified with SPG4 clinical manifestations or asymptomatic with the same genetic variant in heterozygous state.

CONCLUSIONS: We described visual loss and seizures for SPG4 complex phenotype associated with a homozygous variant in the SPAST gene. This diagnosis will lead clinicians to consider it as a differential diagnosis providing adequate genetic counseling.

Keywords: DNA Mutational Analysis, Exome, Spastic Paraplegia, Hereditary, Adolescent, Codon, Nonsense, Consanguinity, Homozygote, Pedigree, Receptors, GABA-A, Siblings, Spastin, Whole Exome Sequencing